This application for a KO2 Independent Scientist Award is submitted to enable me to devote additional time to my research projects and other research-related activities and to further my research career in the field of neuroimmunology of drug abuse. The primary goal of my research is to define the influence of drugs of abuse, such as morphine, on immune responses and their progression. We have previously reported that chronic exposure to morphine suppresses the hypothalamic-pituitary-adrenal (HPA) axis in vivo by desensitizing interleukin- 113(IL- 113)-induced neuronal activation of the hypothalamic paraventricular nucleus, an area of the brain involved in the activation of the HPA axis, thus, inhibiting IL-I f3-induced transcription of corticotropin releasing factor mRNA by the hypothalamus and decreasing the production of anti-inflammatory agents, such as corticosterone, by the adrenal gland. Conversely, we have found that morphine potentiates IL- 1[3-induced immune responses, such as leukocyte-endothelial adhesion (LEA), in mesenteric venules. Thus, it appears that chronic morphine exposure can promote a potentially damaging inflammatory reaction by disrupting the balance between IL-1 [3-mediated local inflammatory responses, such as LEA, and the anti-inflammatory effects of the HPA axis. Recently, my RO1 grant (DA 07058-12) entitled, Morphine actions on the immune system, was renewed for an additional five years (3/15/02-1/31/07), and I was also awarded an equipment grant by the New Jersey Commission on Higher Education to purchase a sequence detection system, a fluorescent imager, and a fluorescent plate reader. The studies in my RO1 project are designed to extend our previous findings to define the mechanisms by which morphine influences the progression of bacterial infection. The Specific Aims are to define the molecular and cellular processes by which bacterial endotoxins modulate mu opioid receptor (MOR)- dependent pathways and how such modulation is related to the progression of endotoxin shock. This KO2 award will enable me to devote maximum time to: 1) working on the aims of my research projects, 2) gaining experience in the use of state-of-the-art methodologies, including real time PCR, fluorescence-based biological assays, and microarray technology, 3) mentoring research students and junior researchers, and 4) establishing an ongoing formal training program in the responsible conduct of research for my lab staff and students.